RU2351312C2 - Pharmaceutical and cosmetic compositions intended for hand nail treatment - Google Patents

Abstract

FIELD: medicine. ^ SUBSTANCE: inventions relate to medicine, namely to dermatology and represents application of formula I compounds: R-O-R1 (I), were R represents linear or branched alkyl residue, which contains 5-8 carbon atoms, and R1 represents formal group or acetyl group. ^ EFFECT: invention ensures improvement of permeability of one or more therapeutic active substances, when using in product, intended for local nail care, which can contain physiologically compatible auxiliary substances. ^ 10 cl, 5 ex

Description

The present invention relates to topical preparations intended for the treatment of nail diseases and nail care, having improved ability to penetrate through the nail substance and skin.

Direct local treatment of nail diseases and nail care practically does not lead to side effects, it is very simple and requires only minimal costs. However, an important task of the direct topical application of compositions for nails is the transfer of a sufficient amount of active substances, including nutrients and anabolic substances, through the nail into the deeper layers of the tissue and into the root of the nail with the complete destruction of the pathogens present and with the entry into the nail of nutrient and anabolic substances. With conventional medications, symptoms can be alleviated with direct local treatment; however, after cessation of treatment, they usually reappear.

Previously, a method has been proposed to improve treatment results with direct topical use of active substances, in which the active substances are used together with the so-called carrier, i.e. a substance which, in addition to the ability to dissolve the active substance well, also has the ability to penetrate well through the substance of the nail and the ability to transport the active substance through the substance of the nail. For example, EP-A-0503988 describes pharmaceutical preparations for the treatment of onychomycosis, which, in particular, contain an active antifungal drug, at least partially, soluble in water, and C ₂ -C ₈ alkanol, linear or branched, as well as an environment comprising at least a third of the water, which is a hydrophilic substance that facilitates the penetration of the antifungal drug through the nail. Penetration enhancers are substances, e.g., glycol, glycol monoether, glycol diether, dimethylsulfoxide, caprolactams, dimethylisosorbide, izopropilidenglitserin, dimethylimidazolidinone, N-methylpyrrolidone-2, pyrrolidone-2, ethyl acetate, glycerides of C ₈ -C ₁₀ polyoxyethylenes and polietilenglikolglitserillaurat and dimethylacetamide .

The method for preparing the compositions described in EP-A-0503988, taking into account the alleged partial solubility of the active substance in water, is suitable only for a limited amount of active substances, i.e. not suitable for many active ingredients.

WO-A-9734644 discloses a composition for topical treatment of nail psoriasis containing n-octanol as a penetration enhancer. Esters of formic and acetic acid are not noted as enhancing the permeability of substances.

The published application WO-A-02-083084 describes preparations for treating nails containing fluconazole, a carrier and a penetration enhancer, preferably caprylic alcohol, tert-amyl alcohol or 3-pentanol. Esters of formic and acetic acid are not noted as enhancing the permeability of substances.

In a publication by Mertin, Dirk et al. Journal of Pharmacy and Pharmacology 49 (3), 241-245, describes a composition comprising chloramphenicol and n-octanol and necessary additives for the manufacture of nail polishes; esters of formic and acetic acid are not described as penetration enhancers.

WO-A-03045339 describes a varnish as a topical preparation for treating mycoses and bacterial infections, moreover, the varnish containing the active agent does not penetrate the nail and any keratin-containing layers. Esters of formic and acetic acid are not described either as a means of improving solubility, or as enhancing the permeability of the substances.

DOS application 10014673 describes an antifungal agent for the treatment of nails in the form of a varnish containing herbal agents and solubility enhancers based on a binder for varnish, for example nitrocellulose.

DOS Application No. 10126501 describes keratin dissolving compositions comprising urea and lower alkanols. Esters of formic and acetic acid are not described as penetration enhancers. In addition, the presence of water is essential.

Other publications, such as, for example, Canadian Patent No. 1072009, are generally distinguished by agents used as solubility enhancers and as permeability enhancers, and neither C ₅ -C ₈ alkanols are used in them.

EP-A-0179675 and WO-A-0200176 describe the preparation of varnishes, oily varnishes and ointments. The use of esters of formic and acetic acid as enhancing the permeability of substances is not noted.

In Derwent No. XP-002310735 describes the preparation of nail polish remover and its use.

All of these compositions differ from the composition proposed in the present invention, the absence of esters of formic and acetic acid as a means of improving solubility or enhancing permeability, on the one hand, and on the other hand, they contain varnish or film-forming additives, such as nitrocellulose. The presence of varnish-forming additives dramatically changes the quality of the composition. The varnish layer prevents the penetration of any component, such as, for example, the active ingredient of the composition.

Currently, there is no satisfactory preparation intended for local treatment of nail diseases and for local nail care containing a carrier that provides the transfer of the required amount of active substance through the nail to the root of the nail (matrix), necessary for successful treatment.

Therefore, the objective of the present invention is to overcome the difficulties associated with the local treatment of nail diseases and local nail care, and obtaining pharmaceutical and cosmetic products that ensure successful treatment.

According to the invention, it was found that the compounds of formula (I)

,

,

wherein

R denotes a linear or branched alkyl residue containing 5-8 carbon atoms, and

R ₁ represents a formyl group or an acetyl group,

not only have excellent ability to penetrate the keratinized substance of the nail and the surrounding skin, but they can also transfer therapeutically active substances, such as, for example, antifungals, antibiotics, antiseptics and corticosteroids, as well as other substances intended for nail care, such as important nutrients through keratinized nails and through the skin.

Therefore, the object of the present invention is a preparation intended for topical use for the treatment of diseases of the nails and for the care of nails, containing

(a) one or more therapeutically or nutritionally active substances,

(b) one or more compounds of formula I

,

,

wherein

R denotes a linear or branched alkyl residue containing 5-8 carbon atoms, and

R ₁ represents a formyl group or an acetyl group,

(c) optionally physiologically compatible excipients.

Permeability enhancing compounds of Formula I of the present invention include formic and acetic acid esters and C ₅ -C ₈ alkanols. The above formula I includes both formates and acetates of linear primary and secondary C ₅ -C ₈ alkanols, as well as their branched analogues, isomeric alkanols. Individual representatives of C ₅ -C ₈ alkanols in formula I are 1-pentanol (amyl alcohol), 3-methyl-1-butanol (isoamyl alcohol), 1-hexanol, 2-hexanol, 4-methyl-1-pentanol, 4- methyl-2-pentanol, 1-heptanol, 2-heptanol, 5-methyl-1-hexanol, 5-methyl-2-hexanol, 1-octanol, 2-octanol, 6-methyl-1-heptanol, 6-methyl- 2-heptanol. Of these primary and secondary C ₅ -C ₈ alkanols, C ₅ -C ₆ alkanols are preferred. Pentanols, in particular 1-hexanol and 2-hexanol, are particularly preferred. Preferred mixtures are mixtures of two or more formates and / or ethyl acetate C ₅ -C ₈ alkanols. Especially preferred is a mixture of esters of hexanols and heptanols, for example, 1-hexanol and 1-heptanol, the mixing ratio may vary from 0.5: 1.5 to 1.5: 0.5. Particular representatives of the formates and acetates of C ₅ -C ₈ alkanols of formula I are amyl formate, amyl acetate, isoamyl formate, isoamyl acetate, 1-hexyl formate, 1-hexyl acetate, 2-hexyl formate, 2-hexyl acetate, 1-heptyl formate, 1-heptyl acetate, 2-heptyl formate, 2-heptyl acetate, 1-octyl formate, 1-octyl acetate, 2-octyl formate and 2-octyl acetate. Preferred C ₅ -C ₈ alkyl esters are C ₅ -C ₈ alkyl acetates. Particularly preferred are C ₅ -C ₆ alkyls. Mixtures of various C ₅ -C ₆ alkyl acetates are even more preferred.

As an object of the present invention for topical preparations, substantially all therapeutically active substances of synthetic and natural origin are considered that are effective in treating nail diseases and periungual diseases. In addition, nutrients and anabolic substances that are effective in nail care are considered as active substances. Suitable therapeutically active substances which may be contained in the topical preparations of the present invention for the treatment of nail diseases are antifungal agents of synthetic and natural origin, antibiotics, antiseptics and corticosteroids, as well as combinations of these active ingredients.

Particularly suitable active substances are antifungal preparations of synthetic and natural origin and nutritional and anabolic substances that are effective in nail care.

Specific examples of therapeutically active substances are:

- antifungal drugs and their physiologically acceptable salts, such as, for example, (±) -cis-2,6-dimethyl-4- [2-methyl-3- (p-tert-pentylphenyl) propyl] morpholine (amorolfine), amphotericin , 6-cyclohexyl-1-hydroxy-4-methyl-2 (1H) pyridinone (piclopyrox), bis-phenyl- (2-chlorophenyl) -1-imidazolylmethane (clotrimazole), 1- [2- (2,4-dichlorophenyl ) -2- (4-chlorobenzyloxy) ethyl] imidazole (econazole), 2,4-difluoro-α, α-bis (1H-1,2,4-triazol-1-ylmethyl) benzyl alcohol (fluconazole), 5-fluorocytosine (flucytosine), 7-chloro-trimethoxymethylspiro- [benzofurancyclohexene] -dione (griseofulvin), 1- [2,4-dichloro-β- (2,6-dichlorobenzene) loxy) phenethyl] imidazole (isoconazole), (±) -1-sec-butyl-4- {4- [4- (4 - {[(2R *, 4S *) - 2- (2,4-dichlorophenyl ) -2- (1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy} phenyl) -1-piperazinyl] phenyl} -4,5-dihydro-1,2 , 4-triazol-5-one (itraconazole), (±) -cis-1-acetyl-4- {4 - ([2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy) phenyl} piperazine (ketoconazole), 1- [2,4-dichloro-β- (2,4-dichlorobenzyloxy) phenethyl] imidazole (miconazole), (E) -N-cinnamyl-N-methyl-1-naphthylmethylamine (naphthifin), nystatin, (E) -N- (6,6-dimethyl-2-hepten-4-ynyl) -N-methyl-1-naphthylmethylamine (terbinafine) , 1 [2 - {(2-chloro-3-thienyl) methoxy} -2- (2,4-dichlorophenyl) ethyl] - 1H-imidazole (thioconazole), O-2-naphthyl-N-methyl-N- (3-tolyl) thiocarbamate (tolnaftate).

Preferred antifungal agents of the present invention are

(±) -cis-2,6-dimethyl-4- [2-methyl-3- (p-tert-pentylphenyl) propyl] morpholine (amorolfine), bis-phenyl- (2-chlorophenyl) -1-imidazolylmethane (clotrimazole ), 1- [2,4-dichloro-β- (2,6-dichlorobenzyloxy) phenethyl] imidazole (isoconazole), 2,4-difluoro-α, α-bis (1H-1,2,4-triazole -1-ylmethyl) benzyl alcohol (fluconazole), (±) -1-sec-butyl-4- {4- [4- (4 - {[(2R *, 4S *) - 2- (2,4-dichlorophenyl ) -2- (1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy} phenyl) -1-piperazinyl] phenyl} -4,5-dihydro-1,2, 4-triazol-5-one (itraconazole), (±) -cis-1-acetyl-4- {4 - ([2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) - 1,3-dioxolan-4-yl] methoxy) phenyl} piperazine (ketoconazole), 1- [2,4-dichloro-β- (2 , 4-dichlorobenzyloxy) phenethyl] imidazole (miconazole), (E) -N- (6,6-dimethyl-2-hepten-4-ynyl) -N-methyl-1-naphthylmethylamine (terbinafine), α- ( 2,4-difluorophenyl) -5-fluoro-β-methyl-α- (1H-1,2,4-triazol-1-ylmethyl) -4-pyrimidinethanol (voriconazole).

Particularly preferred antifungal agents of the present invention are

(±) -cis-2,6-dimethyl-4- [2-methyl-3- (p-tert-pentylphenyl) propyl] morpholine (amorolfine), bis-phenyl- (2-chlorophenyl) -1-imidazolylmethane (clotrimazole ), 1- [2,4-Dichloro-β- (2,6-dichlorobenzyloxy) phenethyl] imidazole (isoconazole), (±) -1-sec-butyl-4- {4- [4- (4- {[(2R *, 4S *) - 2- (2,4-dichlorophenyl) -2- (1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy} phenyl) -1-piperazinyl] phenyl} -4,5-dihydro-1,2,4-triazol-5-one (itraconazole), (±) -cis-1-acetyl-4- {4 - ([2- (2 , 4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy) phenyl} piperazine (ketoconazole).

- antifungal preparations of synthetic and natural origin, such as, for example, essential oils and plant extracts.

Preferred naturally occurring antifungals are tea tree oil (Melaleuca alternifolia), lavender oil (Lavandula officinalis chaix), Australian blue cypress oil (callitis intratropica), and Indian melia leaf extract (Azadirachta indica). These natural antifungal drugs can be used as the sole active substance or in a combination of several active substances. A preferred combination of active ingredients is a mixture of lavender oil, tea tree oil and Australian blue cypress oil.

- antibiotics and their physiologically acceptable salts, such as, for example, α-amino-4-hydroxybenzylpenicillin (amoxicillin), D - (-) - α-aminobenzylpenicillin (ampicillin), 3,3-dimethyl-7-oxo-6-phenylacetamido -4-thia-1-azabicyclo- [3.2.0] -heptane-2-carboxylic acid (benzylpenicillin), benzylpenicillin-benzathine, 3-chloro-7-D- (2-phenylglycinamido) -cephalosporanic acid (pefaclor), 7β - [D-2-amino (4-hydroxyphenyl) -acetylamino] -3-methylcephalosporanic acid (cefadroxil), amino-phenylacetamidomethylcephalosporanic acid (cephalexin), D (-) - threo-2-dichloroacetamido-1- (4-nitrofe nyl) -1,3-propanediol (chloramphenicol), 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (piperazinyl) -3-quinolinecarboxylic acid (ciprofloxacin), (Z) - (2R , 5R) -3- (2-hydroxyethylidene) -7-oxo-4-oxa-1-azabicyclo [3.2.0] heptane-2-carboxylic acid (clavulanic acid), 7-chloro-7-deoxylincomycin (clindamycin), 6-deoxy-5-hydroxytetracycline (doxocycline), 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -1,8-naphthyridine-3-carboxylic acid (enoxacin) , erythromycin, 3- (2-chloro-6-fluorophenyl) -5-methyl-4-isoxazolylpenicillin (fluloxacillin), kanamycin, lincomycin, 7-dimethylamino-6-deoxy-6-des methyltetracycline (minocycline), 6- (2-ethoxy-1-naphthamido) -penicillin (nafcillin), 1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid (nalixidic acid), neomycin, 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -3-quinolinecarboxylic acid (norfloxacin), (±) -9-fluoro-2 , 3-dihydro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-7H-pyrido [1,2,3- (de] [1,4] benzoxazine-6-carboxylic acid ( ofloxacin), 6- (5-methyl-3-phenyl-4-isoxazolocarboxamido) penicillanic acid (oxacillin), 6-phenoxyacetylaminopenicillanic acid (phenoxymethylpenicillin) and 4-dimethylamino octa hydropentahydroxy-1,11-dioxo-6-methylnaphthacene-2-carbamide (tetracycline).

Preferred antibiotics are doxocycline, minocycline and neomycin.

- antiseptics, such as, for example, alkylbenzyldimethylammonium chloride (benzalkonium chloride), N-benzyl-N, N-dimethyl-2- {2- [p- (1,1,3,3, -tetramethylbutyl) -phenoxy] ethoxy} - ethylammonium hydroxide (benzethonium chloride), cetyltrimethylammonium hydroxide (cetrimonium bromide), 1,1'-hexamethylene-bis- [5- (p-chlorophenyl) -biguanide] (chlorhexidine), N ¹ , N ^1- decamethylene-bishydro-amine (4) decalinium chloride), N- (4-chlorophenyl) -N '- (3,4-dichlorophenyl) urea (triclocarbane) and 5-chloro-2- (2,4-dichlorophenoxy) phenol (triclosan).

Preferred antiseptics are, for example, 1,1'-hexamethylene-bis- [5- (p-chlorophenyl) -biguanide] (chlorhexidine).

- corticosteroids and their physiologically acceptable salts, such as, for example, 9α-chloro-16β-methylprednisolone (beclomethasone), 9-fluoro-11β, 17,21-trihydroxy-16β-methyl-1,4-pregnadiene-3,20- dione (betamethasone), 21-chloro-9-fluoro-11β, 17-dihydroxy-16β-methyl-1,4-pregnadiene-3,20-dione (clobetasol), 17,21-dihydroxy-pregn-4-en- 3,11,20-trion (cortisone), 11β, 16α, 17α, 21-tetrahydroxy-1,4-pregnadiene-3,20-dion-16,17-acetonacetal (desonide), 9-fluoro-11β-17, 21-trihydroxy-16α-methylpregna-1,4-diene-3,20-dione (dexamethasone), 9α, 11β-dichloro-6α-fluoro-21-hydroxy-16α, 17α- (isopropylidenedioxy) -pregna-1,4 diene-3,20-dione (flucloronide), 6α, 9α-dif tor-16α, 17α-isopropylidenedioxycorticosterone (fluocinolacetone), 6α, 9α-difluoro-16α, 17α-isopropylidenedioxycorticosterone (fluocinonide), 6α-fluoro-11β, 21-di-isopropyl-16-di-isopropyl dione (fludroxycortide), 3- (2-chloroethoxy) -9α-fluoro-6-formyl-11β, 21-dihydroxy-16α, 17α-isopropylidenedioxypregn-3,5-dien-20-one (formocortal), 21-chloro- 9α-fluoro-11β-hydroxy-16α, 17α-isopropylidenedioxy-4-pregnen-3,20-dione (galcinonide), 17α-hydroxycorticosterone (hydrocortisone), 11β, 17,21-trihydroxy-6α-methyl-1,4- pregnadiene-3,20-dione (methylprednisolone), 11β, 17,21-trihydroxy-pregna-1,4-d yen-3,20-dione (prednisone), 17α, 21-dihydroxypregna-1,4-diene-3,11,20-trion (prednisone), 9-fluoro-16α-hydroxyprednisolone (triamcinolone) and triamcinolone-16α, 17 -acetonide (triamcinolone acetonide).

Preferred corticosteroids are 11β, 16α, 17α, 21-tetrahydroxy-1,4-pregnadiene-3,20-dion-16,17-acetonacetal (desonide), 9α, 11β-dichloro-6α-fluoro-21-hydroxy-16α, 17α- (isopropylidenedioxy) -pregna-1,4-diene-3,20-dione (flucloronide), 6α, 9α-difluoro-16α, 17α-isopropylidenedioxycorticosterone (fluocinolone ketonide), 6α, 9α-difluoro-16α, 17α-isopropidone fluocinonide), 6α-fluoro-11β, 21-dihydroxy-16α, 17-isopropylidenedioxy-4-pregnen-3,20-dione (fluroxycortide), 3- (2-chloroethoxy) -9α-fluoro-6-formyl-11β, 21-dihydroxy-16α, 17α-isopropylidenedioxypregna-3,5-dien-20-one (formocor tal), 21-chloro-9α-fluoro-11β-hydroxy-16α, 17α-isopropylidenedioxy-4-pregnen-3,20-dione (galcinonide), triamcinolone-16α, 17α-acetonide (triamcinoloneacetonide).

Specific examples of combinations of active substances are:

- combinations of corticosteroids with antifungal drugs, antibiotics or antiseptics. A preferred combination is, for example, (±) -cis-1-acetyl-4- {4 - ([2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolane -4-yl] methoxy) phenyl} piperazine (ketoconazole) and 11β, 16α, 17α, 21-tetrahydroxy-1,4-pregnadien-3,20-dione-16,17-acetonacetal (desonide).

- combinations of antifungal drugs of synthetic origin with antifungal drugs of natural origin.

A preferred combination is bis-phenyl- (2-chloro-phenyl) -1-imidazolylmethane (clotrimazole) with tea tree oil.

- combinations of various antifungal drugs of natural origin. The preferred combination is lavender oil, tea tree oil and Australian blue cypress oil.

Suitable nutritional active ingredients of the present invention are, in particular, vital nutrients and anabolic substances selected from the group consisting of amino acids, vitamins and minerals.

Preferred amino acids are (S) -2,6-diaminohexanoic acid (lysine), ®-2 amino-3-methaptopropionic acid (cysteine), and in particular 2-pyrrolidinecarboxylic acid (L-proline). In the case of L-Proline, an anabolic substance was found that was found to be suitable for nail care and treatment. To date, L-Proline has been noted only as an optional component of cosmetics intended for nail care, containing sulfonated amino acids or their derivatives as an active component (EP-A-0534810).

Preferred vitamins are cis-2- (4-carboxybutyl) -3,4-ureidotetrahydrothiophene (biotin), (±) -2,4-dihydroxy-N- (3-hydroxypropyl) -3,3-dimethylbutyramide (panthenol), D (+) - 2,4-dihydroxy-N- (3-hydroxypropyl) -3,3-dimethylbutyramide (dexpanthenol).

Preferred minerals are inorganic and organic compounds of calcium, magnesium and zinc, in particular organic salts such as glycerophosphates and lactates.

Specific combinations of vital nutrients and anabolic substances are:

- combinations of 2-pyrrolidinecarboxylic acid (L-proline) with one or more additional nutrients and anabolic substances selected from the group consisting of amino acids, vitamins and minerals. Preferred combinations of 2-pyrrolidinecarboxylic acid (L-proline) with one or more nutrients and anabolic substances are combinations of m (S) -2,6-diaminohexanoic acid (lysine), (R) -2-amino-3-mercaptopropionic acid (cysteine), gelatin, cis-2- (4-carboxybutyl) -3,4-ureidotetrahydrothiophene (biotin), (±) -2,4-dihydroxy-N- (3-hydroxypropyl) -3,3-dimethylbutyric acid ( panthenol), D (+) - 2,4-dihydroxy-N- (3-hydroxypropyl) -3,3-dimethylbutyric acid (dexpanthenol) and inorganic and organic compounds E calcium, magnesium and zinc.

The topical preparations of the present invention, in addition to one or more active substances and one or more compounds of formula I, contain physiologically compatible excipients. Suitable substances of this kind are, for example, terpenes and oils containing terpenes, alcohols, ketones, fatty acid esters, polyglycols, surfactants, urea, antioxidants and complexing agents.

Suitable terpenes are acyclic, monocyclic and bicyclic terpenes, as well as oils containing these terpenes. Examples of acyclic terpenes are acyclic terpene hydrocarbons, such as, for example, myrcene, acyclic terpene alcohols, such as, for example, citronellol and geraniol, as well as acyclic terpene aldehydes and ketones, such as, for example, citral, α-ionone and β-ionon . Examples of monocyclic terpenes are monocyclic terpene hydrocarbons, such as, for example, α-terpene, γ-terpene and limonene, monocyclic terpene alcohols, such as, for example, thymol, menthol, cineole and carvacrol, as well as monocyclic terpene ketones, such as, for example , menton and carvon. Examples of bicyclic terpenes are karan group terpenes, such as, for example, caron, pinan group terpenes, such as, for example, α-pinene and β-pinene, as well as borne group terpenes, such as, for example, camphor and borneol. Particularly suitable terpenes are monocyclic terpene alcohols, such as, for example, thymol and menthol. Examples of suitable terpene-containing oils are peppermint oil, cardamom oil, geranium oil, rose oil, thuja oil and thyme oil. Particularly suitable oils are peppermint oil, lavender oil and thyme oil.

Suitable alcohols are branched and unbranched alcohols containing from 1 to 3 hydroxy groups and from 2 to 6 carbon atoms, the hydroxy groups are optionally partially or completely converted to ether or ester groups. Particularly suitable alcohols are ethanol, 1-propanol, 2-propanol (isopropanol), 1,2-propanediol (propylene glycol), 2-phenylethanol (phenethyl alcohol), 1-butanol (butyl alcohol), ethylene glycol monomethyl ether (methoxyethanol), monophenyl ethylene glycol ether (phenoxyethanol), 1,2,3-trihydroxypropane (glycerin), ethyl acetate, butyl acetate, glycerol diacetate (diacetin) and glycerol triacetate (triacetin).

Suitable ketones are, for example, acetone and methyl ethyl ketone (2-butanone).

Suitable are esters of acids, esters of saturated and unsaturated, branched and unbranched fatty acids containing from 8 to 21 carbon atoms, in which the alcohol component is branched and unbranched alcohols containing from 1 to 6 carbon atoms. Particularly suitable fatty acid esters are tridecanecarboxylic acid isopropyl ester, tetradecanecarboxylic acid isopropyl ester (isopropyl myristate), pentadecanecarboxylic acid methyl ester and 9-octadecenoic glycerol monoester (glycerol monooleate).

A suitable polyglycol is, for example, polyglycol 400.

Suitable surfactants are, for example, nonionic surfactants. Particularly suitable surfactants are partial esters of fatty acids and sorbitan (span), partial esters of fatty acids and polyoxyethylene sorbitan (tween), partial esters of fatty acids and polyoxyethylene (myrj) and ethers of alcohols and polyoxyethylene (brij).

Suitable antioxidants are, for example, butylhydroxytoluene (BHT), butyl 4-methoxyphenol (BHA), tocopherols and ascorbates.

Suitable complexing agents are, for example, ethylenediaminetetraacetic acid (EDTA) and disodium salt of ethylenediaminetetraacetic acid (Na ₂ -EDTA).

As topical preparations of the present invention, for example, solutions, tinctures, emulsions, gels, ointments, creams and pastes are considered. Preferred topical forms are solutions. To obtain solutions in certain active ingredients, such as proline, the presence of small amounts of water is necessary together with a means of improving solubility as a stabilizer (to prevent discoloration). Suitable solubility enhancers are low activity alkanols such as methanol, ethanol, propanol and isopropanol, as well as acetone.

The present invention also relates to a method for the preparation of topical preparations of the present invention, which is characterized in that the individual components are uniformly mixed and optionally heated (to a maximum of 80 ° C), mixed until a homogeneous solution is obtained. The resulting solution is preferably directly used for topical application. However, the solution can also be converted to another topical form by the addition of other physiologically acceptable excipients using conventional dissolution, mixing and suspension procedures.

The topical preparations of the present invention are preferably used in the form of a solution. Preferred topical formulations of the present invention comprise

from 0.1 to 20 wt.% one or more active substances,

from 1 to 99.90 wt.% one or more compounds of formula I and

from 0 to 98.90 wt.% one or more compatible excipients.

The present invention also relates to the use of topical preparations of the present invention for the treatment, prevention, subsequent treatment and supportive treatment of nail diseases and periungual diseases, as well as for nail care. In addition, the present invention relates to the use of the preparations of the present invention for the treatment of mycotic infectious diseases of hooves, paws and claws of domestic animals and domestic animals.

Topical preparations containing antifungal drugs are, for example, applicable for the following purposes:

- treatment, prevention and subsequent treatment of onychomycosis caused by dermatophytes, yeast or fungi, or mixed infections,

- treatment, prevention and subsequent treatment of fungal infections of the nails in patients suffering from psoriasis, diabetes or AIDS,

- supportive treatment of periungual infections, such as, for example, Candida paronychium.

Topical preparations containing antibiotics are, for example, applicable for the following purposes:

- supportive treatment and / or prevention of fungal infections of the nails and periungual infections caused by bacteria.

Topical preparations containing antiseptics are, for example, applicable for the following purposes:

- treatment and prevention of fungal infections of nails and periungual infections caused by nonspecific or unidentified pathogens.

Topical preparations containing corticosteroids or combinations of corticosteroids with antifungal drugs, antibiotics or antiseptics are, for example, applicable for the following purposes:

- treatment, prevention, subsequent treatment and supportive treatment of psoriasis of the nails and other inflammatory conditions of the nails and periungual areas.

The topical pharmaceutical preparations of the present invention are useful for the treatment of diseases of the nails and periungual diseases of the nails of the fingers and toes, as well as for the treatment of diseases of the hooves, paws and claws of pets and pets. The frequency of use of pharmaceuticals depends on the severity and location of the disease. Usually, 1 to 3 times a day is sufficient. The solution is applied directly to the affected nail or hoof, paw or claw and, if necessary, to the surrounding affected areas of the skin. To prevent relapse, treatment should be continued for approximately another two to four weeks after laboratory tests do not indicate the absence of traces of fungi, spores and other pathogens.

Topical cosmetics of the present invention containing one or more nutrients and anabolic substances are suitable for nail care, such as, for example, atrophy of the nails of the toes and hands. Types of nail atrophy include, for example, brittleness, brittleness and thinning of nails, as well as white stripes and dots. The drug is applied to cosmetically unattractive nails, and, if necessary, to the surrounding areas of the skin. The frequency of use of the drug depends on the severity and location of atrophy. Usually, 1 or 2 times a day is sufficient.

The topical preparations of the present invention have the advantage that they enter the affected nail together with the active substance for several days and exert their effect on the nail bed and the root of the nail. Due to the faster onset of exposure and better penetration, treatment of nail diseases usually ends in about 2-4 months. In this case, the patient adheres to the treatment regimen, since the duration of treatment required when using other methods is significantly reduced. With skin diseases and especially near the nail sections of the skin, healing and nutritional effects begin faster, since the active substance in sufficient quantity and quickly penetrates the skin. Nail care, as a rule, should be carried out within a month. To maintain a healthy state of the nails, a substance intended to care for them can be used for a longer period of time.

The present invention can be represented using the following examples:

Example 1: A solution of Australian blue cypress oil, tea tree oil and lavender oil concentration of 6%

Australian Blue Cypress Oil 2.0 g Tea tree oil 2.0 g Lavender oil 2.0 g Isoamyl acetate 94.0 g

The mixture is stirred until a homogeneous solution is obtained.

Example 2: a solution of proline concentration of 2.0%

L-proline 2.0 g Water (deionized) to 2.0 g Ethanol 48.0 g Amyl acetate 48.0 g

With stirring, L-Proline is dissolved in ethanol and a small amount of water. Amyl acetate is then added and mixed until a homogeneous solution is obtained.

Example 3: A solution of amorolfine concentration of 1%

Amorolfin 1.0 g Ethanol 10.0 g 1-hexyl acetate 89.0 g

Amorolfin is added to a mixture of ethanol and hexyl acetate with stirring until a homogeneous solution is obtained.

Example 4: a solution of terbinafine concentration of 1%

Terbinafine base 1.0 g Isoamyl acetate 99.0 g

The substances are weighed into a glass and mixed until a homogeneous solution is obtained.

Example 5: Cream with amyl acetate

H ₂ O deionized 720 g Carbopol Ultrez 10 9.6 g Glycerol 24.0 g Sunflower oil 216.0 g Emulgade 1000NI 45.6 g Lanette n 9.6 g Amyl ether 36.0 g Phenonip 9.6 g Triethanolamine

With stirring, the carbopol is dispersed in H ₂ O and allowed to soak. Glycerin is added and heated to + 50 ° C.

With stirring and heating to 70 ° C, a clear solution of sunflower oil, emulsifier and Lanette is obtained.

Amyl ether is added to the fat paste and, with vigorous stirring, homogenized with a water-based paste. With stirring, Phenopip is added.

Cool the cream and adjust the pH to 5.5 with triethanolamine.

Claims (10)

1. The use of compounds of formula I

,
in which R denotes a linear or branched alkyl residue containing 5-8 carbon atoms, and
R ₁ denotes a formyl group or acetyl group, to improve the permeability of one or more therapeutically active substances when used in a product intended for local nail care, which may contain physiologically compatible excipients. 2. The use of compounds of formula I

,
in which R denotes a linear or branched alkyl residue containing 5-8 carbon atoms, and
R ₁ is a formyl group or an acetyl group, in a topical product for the treatment of nail diseases, where the compounds of formula I are added to improve the permeability of one or more therapeutically active substances and where the product may contain physiologically compatible excipients. 3. The use according to claims 1 and 2, characterized in that amyl formate or amyl acetate is used as a solubilizing agent of the formula (I). 4. The use according to claims 1 and 2, characterized in that 1-hexyl formate or 1-hexyl acetate is used as a solubilizing agent of the formula (I). 5. The use according to claims 1 and 2, characterized in that 1-heptyl formate or 1-heptyl acetate is used as a solubilizing agent of the formula (I). 6. The use according to claims 1 and 2, characterized in that 2-heptyl formate or 2-heptyl acetate is used as a solubilizing agent of the formula (I). 7. The use according to claims 1 and 2, characterized in that 1-octyl formate or 1-octyl acetate is used as a solubilizing agent of the formula (I). 8. The use according to claims 1 and 2, characterized in that use 2-octyl formate or 2-octyl acetate as a solubilizing agent of the formula (I). 9. The use according to claims 1 and 2, characterized in that one or more excipients are selected from the group consisting of terpenes and oils containing terpenes, alcohols, ketones, fatty acid esters, polyglycols, surfactants, urea, antioxidants and complexing agents. 10. The use according to claims 1 and 2, characterized in that they use one or more therapeutic active substances selected from the group comprising synthetic or natural antifungal drugs, antibiotics, antiseptics and corticosteroids.